The regions of contact between deoxyhemoglobin S tetramers in the crystal form have been analyzed with a computer graphics system. Peptides complementary to two of these contact regions have been projected and their interactions with the hemoglobin analyzed visually. Several of these peptides have been synthesized by solid-phase and solution methods and purified and characterized. These peptides have been tested on the kinetic and solubility assays of deoxyhemoglobin S gelation. All, so far, have a negative effect, probably due to excluded volume. New peptides are being designed and synthesized using energy minimization and other considerations to enhance their potential effectiveness as inhibitors of sickling. To study in more detail the mechanism of excluded volume, we have tested a variety of short homopolymers of the most soluble amino acids. It has been found that lysine and serine peptides have the effect on activity coefficient predicted from their weight fraction; proline, however, has a lesser effect, suggesting a specific molecular interaction.